Cytochrome P450 aromatase, is the last enzyme in estrogen biosynthesis, catalyzing the conversion of androgens to estrogen. It plays a major role in the sexual differentiation of the brain during development and has been implicated in the brain response to injury and in the pathophysiology of Alzheimer's disease. The enzyme is highly expressed in liver, steroidogenic organs and specific regions of the brain including the amygdala, in the bed nucleus of the stria terminalis, the preoptic area (POA) and anterior hypothalamus. Moderate or lower levels have been observed in many other brain regions including posterior and lateral hypothalamic nuclei, hippocampus and temporal cortex of rodents, non-human primates and humans.
Aromatase activity can be inhibited reversibly or irreversibly by steroidal as well as non-steroidal compounds. Non-steroidal and steroidal aromatase inhibitors are used as adjuvant therapies for post-menopausal women having estrogen-dependent breast cancer. Examples of non-steroidal aromatase inhibitors approved for such use include letrozole (Femara®) and anastrozole (Arimidex®). These drugs have been shown to reduce the rate of recurrence of cancer in treated patients.
Aromatase inhibitor drugs are also used by body builders and athletes who abuse anabolic steroids, as a means of limiting the estrogenic side effects of excess androgens.
Radiotracer compounds that interact with the physiological targets of these drugs are useful for developing new forms of aromatase inhibitors as well as for monitoring the treatment efficacy of the drugs and for adjusting dosages.
Radiotracer compounds that specifically interact with P450 aromatase enzymes are further useful for studies on the location of the enzyme in tissue samples, for studying the enzyme mechanism of action and for kinetic studies on the synthesis and turnover of the enzyme in tissues.
Previous attempts to make use of [N-methyl-11C]vorozole as a reliable, highly specific imaging tracer in positron emission tomography (PET) studies have been inexplicably unsuccessful, with the radiotracer exhibiting low regional specificity and high non-specific binding (see Lidström, et al. (1998) Nucl. Med. Biol. 25:497-501; Takahashi, et al. (2006) Neuroreport 19:431-435).
In addition, an attempt to make use of [11C] as a specific radiotracer for studying brain aromatase enzymes in vivo (Kil, et al. (2008) J. Nucl. Med. 49 (Sup. 1):285P) found that the tracer was rapidly taken up in the brain and was then rapidly cleared. Pretreatment with unlabeled letrozole failed to block uptake. The rapid clearance of the [11C]letrozole and lack of specific binding indicated that it was not a useful radiotracer for brain aromatase activity.
Thus, previous attempts to use radiotracer-labeled aromatase inhibitors to study aromatase activity in the brain and other tissues have been relatively, but inexplicably, unsuccessful.